There is currently no vaccine or standard treatment for RSV. However there is clearly an unmet medical need: RSV is responsible for approximately 100,000 hospitalizations per year in the U.S. alone, and is globally responsible for more than 150,000 deaths per year. The continued absence of vaccines and standard treatments for RSV disease represents an important and serious gap in preventive medicine. In response to RFA AI-09-016, investigators from St. Jude Children's Research Hospital, Novartis Vaccines and Diagnostics, Inc., and Le Bonheur Children's Medical Center are proposing a partnership to expedite RSV vaccine development. Recombinant murine Sendai virus (SeV) expressing RSV F glycoprotein (rSeV-RSV-F) is an extremely attractive candidate for an RSV vaccine. This xenotropic vaccine elicits rapid and durable protection against RSV in an animal model and is associated with no enhanced immunopathology upon RSV infection. Since an RSV vaccine will need to protect infants, and since maternal antibodies can reduce the efficacy of replicating and non-replicating vaccines, fundamental questions concerning vaccine-antibody interactions must be addressed prior to clinical development of rSeV-RSV-F. Our Central Hypothesis is that the rSeV-RSV-F vaccine will confer RSV protection to infants, even in the presence of maternal antibodies. Our Specific Aims are: (1) To determine the relative functional titers of anti-SeV (PIV1) and anti-RSV antibodies in human infants, (2) To determine the influence of maternal antibodies on rSeV-RSV-F vaccine efficacy (in a cotton rat model), and (3) To optimize vaccine by formulation and regimen. When optimized vaccine doses/formulations/regimens are identified, these will be further tested: (i) to ensure the absence of enhanced immunopathology, (ii) to measure response durability, and (iii) to measure immune correlates of protection. Data from these experiments will have broad application to the pediatric vaccine field, and will be critical to the launch of clinical trials with rSeV-RSV-F.